The effectiveness and safety of Iranian herbal medicines for treatment of premenstrual syndrome: A systematic review.

Objective
Premenstrual syndrome (PMS) is one of the most common problems among women of reproductive age. The popularity of complementary/alternative therapies has grown in recent years, and these treatments have been more commonly used by women (48.9%) than men (37.8%). The aim of this systematic review was to assess effectiveness and safety of Iranian herbal medicines for treatment of premenstrual syndrome.


Methods
PubMed, Scopus, Cochrane, and Google Scholar were searched along with SID, Magiran and Irandoc up to Dec 2017.Inclusion criteria consist of Iranian, published, randomized controlled trials (RCTs) using Iranian herbal medicine for treatment of reproductive age women with PMS. Eventually Eighteen RCTs met the inclusion criteria.


Results
Overall, studies have shown that Vitex agnuscastus, Hypericum perforatum,Matricaria chamomilla, saffron, Curcumin, Melissa officinalis, Zataria multiflora,Wheat Germ Extract, Echinophora platyloba, Foeniculum vulgare, Valerian root extract,Citrus sinensis, Zingiber officinale and Flax seed might alleviate symptoms of PMS.


Conclusion
This research demonstrated efficacy and safety of Iranian herbal medicines in alleviating PMS. Therefore, herbal medicine can be regarded as an alternative treatment for women suffering from PMS.


Introduction
Premenstrual syndrome (PMS) is one of the most common problems among women of reproductive age (Lethaby et al., 2012, Taavoni et al., 2014. This syndrome was first characterized in 1931 by Frank and Horney (Filho et al., 2011). PMS refers to a set of psychological and physical symptoms such as depression, hopelessness, anxiety, mental tension, emotional disturbances, violence , face blushing, low desire to do routine jobs, distraction, reduction of energy, rapid fatigue, changes in diet, sleep disturbances, abdominal pain, breast tenderness, headache, muscles cramp, fatigue, edema and weight gain which are experienced by a few women in the late luteal phase (Lentz andHenshaw 2007, Hankinson et al., 2010). About 80-90% of women experience PMS before menstrual bleeding. Premenstrual dysphoric disorder (PMDD) is known as extreme sort of PMS which affects the person's daily activities. It is recognized in 3-5% of women ( Stutz et al.,2011, Tolossa andBekele 2014). In Iran, the prevalence of PMS is 67-78.4% (Soltan Ahmadi et al., 2007Ahmadi et al., , kiani et al., 2009. Moreover, PMS is more common among white women, smokers, obese, and youthful women (Masho et al., 2005). This syndrome has a multifactorial etiology which is not completely characterized. At first, PMS is mainly associated with diminished levels of progesterone in the luteal phase (Speroff and Fritz 2010). Different etiologies described for PMS include abnormal neurotransmitter reactions to ordinary ovarian functions, hormonal imbalances, sodium retention, and/or nutritional deficiencies (Dickerson et al., 2003). The manifestations of PMS may be adequately serious to disturb women's regular functioning, quality of life, social relationships and can lead to increased rates of suicides, accidents, joblessness, work and school absenteeism, and poor scholastic execution, (Mishell 2005, Lowin et al., 2011. Besides, reproductive health problems such as child abuse and domestic violence have also been observed in families with individuals experiencing PMS. Therefore, this syndrome not only influences the individual herself, but also affects the family and even the society (Pinar et al., 2011). Based on the literature, many different pharmacological and non-pharmacological treatments have been recommended as possible therapies for women with PMS (Kessel, 2000;Moline and Zendell, 2000;Stevinson and Ernst, 2001;Douglas, 2002;Girman et al., 2003;Rapkin, 2003;Wong et al., 2010;Hur et al., 2011;Vishnupriya and Rajarajeswaram, 2011;Zamani et al., 2012, Samadi et al., 2013Delaram, 2014;Saki et al., 2015) because of uncertainty of its pathogenesis, the extensive variety of its signs, and a large placebo impact. For example, selective serotonin reuptake inhibitors (SSRIs) have been evaluated as a first-line therapy for PMS (Steiner et al., 2006). Despite this fact that PMS symptoms relief is ambiguous, it is rational to propose healthy lifestyle changes which may have general advantages (Douglas 2002, Girman et al. 2003, Rapkin 2003. For long period of time, plants have been assumed as important treatments for numerous ailments, particularly in Eastern nations (Fallah Huseini et al., 2006). Medicine has always played a significant role in Iranian culture and civilization. Due to its long history and hundreds of publications, Iranian traditional medicine is among the oldest and richest alternative medicines (Emtiazi, 2012 ). Since Iran has a wide variety of medicinal plants and also as Iranians are interested in using them, herbal medicine has become increasingly popular among Iranian population (Ghasemi dehkordi et al, 2003). Also, these days, complementary medicine and herbal products is more commonly used by women (48.9%) than men (37.8%) (Amasha et al. 2017). Therefore, Iranian researchers have investigated the effects of various native herbal medicines for treatment of PMS (Domoney et al., 2003); however, there is no evidence indicating the safety of different herbs or reporting their adverse events, so a review study is required for access to reliable and evidence-based information (Younesi, 2014). To the best of our knowledge, the efficacy of Iranian herbal medicine in treatment of PMS has not been systematically assessed. This systematic review aimed to examine the effectiveness and safety of Iranian herbal medicines for treatment of PMS based on the articles published in this field.

Materials and Methods
A systematic literature review was conducted utilizing the electronic databases such as Pub Med, Scopus, Cochrane and Google Scholar as well as Persian databases such as SID, Magiran and Irandoc up to Dec 2017 using appropriate keywords including "Premenstrual Syndrome or PMS"AND "alternative medicine, Complementary Therapies, medicinal plants, Herbal medicine, Herbal Remedies, Plant Extracts, Iranian Herbal Medicines"in the "title", "abstract", or "keywords", until Dec 2017. All databases were searched for Iranian published randomized controlled trials (RCTs). Duplicate articles, or articles which were inconsequential to the investigation, were not considered in the review. Moreover, reference section of relevant trials, systematic reviews and meta-analyses were checked to recognize further trials missed by electronic search. In the process of article extraction, one of the analysts checked both the title of the article and the abstract and judged its appropriateness for inclusion.
If the selected articles met the following criteria, they were included in this review: 1) Conducted on the humans. 2) Being a randomized controlled trial (RCTs).
3) Performed by Iranian authors using Iran native plants. 4) Female participants of reproductive age with premenstrual disorders who experienced at least one symptom happening periodically during day 0 to 14 before menstruation, for at least three menstrual cycles. 5) Interventions consisted of any formulation of Iranian herbal medicine including oral preparations, decoctions, injections, and tablets. Comparison groups could comprise of a placebo or some other interventions. Evaluations of the effect of a specific herbal medicine versus another herbal medicine were also included. 6) Outcome measures included: Primary outcomes: Change of general manifestations by Daily Symptom Record (DSR), prospective record of the impact and severity of menstrual symptoms (PRISM) calendar, shortened premenstrual assessment form (SPAF), visual analogue scale (VAS) that is a rapid and straightforward assessment and ranging from 0 (no symptoms) to 10 (unbearable) and assess following six symptoms (headache, nervousness, restlessness, depression, breast swelling and pain, bloating and tympani) (Zamani etal., 2012) and Premenstrual Syndrome Screening Tool (PSST). The following tools were considered for Secondary outcomes: 1. Quality of life 2. Adverse events 3. Daily form of MAPMS (Mastalgia intensity Associated with PMS) 4. Hamilton Depression Rating Scale 5. GHQ-28 questionnaire 6. The Beck Depression Inventory (BDI) The process of the search and selection of RCTs is shown in Figure1. The articles selection and data analysis were undertaken by two researchers. Based on the search results, authors browsed the abstracts and relevant records. Full articles were retrieved for all conceivably significant trials. All articles were scrutinized to check for multiple publications on the same trials. For each study, we extracted the following data according to a pre-defined checklist: first author, year, design, study period, subjects' age, intervention, control, number of participants in intervention and control groups, baseline comparability, dropout, tools, blinding method, adverse effect, outcomes and quality of trials which evaluated by two reviewers using Oxford Center for Evidence-Based Medicine checklist for therapeutic studies. Data were independently assessed by two authors and incongruities were settled by discussion with a third researcher. Overall, there was complete agreement between the two reviewers. The characteristics of the included studies are shown in Table 1.

Quality assessment of the included studies
The quality of the included studies was assessed by Oxford Center for Evidence-Based Medicine checklist for RCTs (see Table2).
List of criteria for surveying the quality of studies consist of: A: Was the assignment of patients to treatments randomized? B: Were the groups similar at the beginning of the trial? C: Aside from the allocated treatment, were groups treated equally? D: Were all patients who entered the trial accounted for? -And were they analyzed in the groups to which they were randomized? (1: Losses to follow-up and 2: intention-to-treat) E: Were measures objective or were the patients and clinicians kept "blind" to treatments?
F: What were the results? (www.cebm.net/ University of Oxford).

Results
From 604 relevant trials, 18 RCTs met the inclusion criteria. The characteristics of included studies summarized in Table 1.

The effect of Matricaria chamomila (Chamomile) extract on PMS Chamomile vs. Mefenamic Acid
Sharifi et al. compared two groups treated with chamomile and mefenamic acid (MA), and a significant decrease (p<0.0001) was found in average mastalgia when comparing pre and postintervention after first and second cycles in those treated with chamomile extract (10.5±21.7 and 13.7±20.4 percent) and among MA-treated subjects (12.1±24.7 and 13.8±24 percent). However, there was no significant difference in PMS symptom in chamomile extract and MA groups after first and second cycles (p>0.05). The side effects after two periods of treatment included menstrual bleeding in nine (20%) patients receiving chamomile (Sharifi et al., 2014).

The effect of Crocus sativus L. (saffron) on PMS
Agha-Hosseini et al. assessed the effect of saffron on the PMS using two-way repeated measures analysis of variance to assess the differences within and between groups that demonstrated a significant impact of saffron on the Total Daily Symptom Ratings (p<0.0001). In saffron group, post-hoc correlations demonstrated a significant change from cycle 3. A significant difference between cycles 3 and 4 was seen in the saffron group (p<0.001). The difference between the two protocols was significant at cycle 4 (t=5.92, df=48, p<0.001). In addition, oneway repeated measures analysis of variance demonstrated a significant impact of saffron on Hamilton Depression Rating Scale (p<0.0001). In saffron group, posthoc correlations demonstrated a significant change from cycle 3. A significant differences between cycles 3 and 4 were seen in the saffron group (p<0.001). The difference between the two protocols was significant at cycle 4 (t=8.99, df=48, p<0.001). Six adverse effects were seen in this trial. The difference between the saffron and placebo in the recurrence of adverse impacts was not significant ( Table  2). None of adverse impacts was severe. Appetite changes and headache were more common in the saffron group, yet not noteworthy (Agha-Hosseini, Kashani et al. 2008) In another trial, Pirdadeh Beiranvand et al., using repeated measures test, showed that the difference in the severity of PMS symptoms over time in the intervention group (p<0.001) and in the control group (p=0.04) were statistically significant; also, in terms of time-group interaction, a significant difference in changes of the mean severity of PMS was shown between the two groups over time (p<0.001). Chi-square test indicated no significant differences in terms of side effects such as increased appetite, loss of appetite, sedation, nausea, headache, and euphoria between the two groups (p>0.05) (Beiranvand et al., 2015). The mean reduction in severity of PMS score was 6.79 in intervention, and 8.82 in placebo group which did not show any significant difference between the groups (p=0.157). Although Wilcoxon test showed that the severity of PMS score reduced significantly in both groups after the intervention. (In intervention group: Z=3.58, p=0.0001; in placebo group: Z=4.2, p=0.0001) The frequency of reported symptom score decreased from 84.13 in the first menstrual cycle to 56.5 in the fourth cycle in intervention group but this decrease was not significantly different in intervention and placebo groups All the symptoms showed a significantly greater improvement with the fennel extract than placebo (p<0.05) except bloating which was unaffected by the treatment. A significant difference was observed in mean premenstrual mood (p<0.001) and behavioral (p<0.001) symptoms severity of in the intervention group before and after the intervention the difference in mean of mood and behavioral symptoms before the intervention, and one, two, and three months after the intervention in the intervention group was significant (p<0.001). The PMS improved significantly in both intervention groups during the first and the second month after the intervention. In the Vitexagnus and Flaxseed groups, the mean total PMS score were significantly lower than that in the control group at the first months. In the second month There was no significant difference between the Vitexagnus and Flaxseed groups in terms of the PMS score.  (Khayat et al., 2015).

The effect of Melissa officinalis on PMS
Study by Akbarzadeh et al., showed progressive decline in the mean of PMS symptoms (physical, Psychological and Social) in M. officinalis-treated group (42.56±15.73, 30.72±13.24, 30.2±12.08, 13.90±10.22) at baseline, as well as 4, 8 and 12 weeks after trial and the differences were statistically significant (p<0.0001). Using paired t-test, it was demonstrated that the force of physical, psychological and social symptoms significantly diminished in the intervention group. However, no significant difference was found in the control group in this regard (p<0.001). No side effects related to M. officinalis plant were noted in this study (Akbarzadeh et al., 2015).

The effect of Zataria multiflora on PMS
Sodouri et al., reported a nonsignificant difference between Intervention and Placebo groups in terms of reductions in the mean of PMS severity score (p=0.157). Wilcoxon test demonstrated that the severity of PMS score decreased significantly in both groups after the intervention (In intervention group: Z=3.58, p=0.0001; in placebo group: Z=4.2, p=0.0001). The repeated-measure analysis of variance revealed that the recurrence of symptom score markedly diminished in the menstrual cycles; however, this decline was not significantly different in intervention and placebo groups (p=0.35) (Sodouri et al., 2013). The severity of the general and psychological symptoms diminished in two groups, yet this reduction was significantly more pronounced in the wheat germ extract group (p<0.001). The decrease in severity of physical symptoms was statistically significant just in the wheat germ extract group (p<0.001), and there was not a statistically significant difference in the placebo group. A considerable reduction in severity of symptoms following two months of treatment observed in fatigue (85.32%), irritability (84.80%), palpitation (80.24%), irritation (80.24%), breast tenderness (79.71%), headache (76.52%), sleep problems (73.79%), increased appetite (73.12%), acne (70.40%), mood swings (69.64%), food cravings (68.71%), wish to be alone (68.10%), depression (61.64%), forgetfulness (59.15%), anxiety (58.94%), poor concentration (56.72%), crying (44.53%) and breast swelling (25.72%). The number of consumed painkillers remarkably reduced after intervention in these cases (p<0.001); Complications were not announced in 95.2% of the wheat germ extract group and 92.9% of the placebo group (Ataollahi et al., 2015).

The effect of Vitex agnus-castus on PMS Vitex agnus-castus vs. placebo
Three trials (Zamani et al., 2012, Moosavi et al., 2014, Mirghafourvand et al., 2015 investigated the effect of Vitex agnus-castus on PMS. Zamani et al. reported a reduction in a large portion of the PMS VAS scores in two groups, in any case it was more significant in the Vitex agnus group (p<0.0001). Mann-Whitney test indicated that Mean Rank of differences in the headache, nervousness, restlessness, depression, breast pain and swelling, swelling and tympani was significantly different between pre-and post-treatment in both groups and between two groups (p<0.0001). No adverse effect was addressed. Another trial performed by Mousavi et al. showed that mean scores of PMS physical symptoms (p<0. 001) and PMS psychological symptoms (p<0. 05) were significantly different between two groups in the second and third cycles of treatment. The mean duration of PMS was significantly different between the two groups (p<0. 01). Some adverse effects were reported in two subjects of intervention group including itching, rash and dizziness and in one subject of the control group, stomachache and diarrhea were seen.

Vitex agnus castus vs. Flaxseed
Three groups was investigated in Mirghafourvand et al. study and finding showed; PMS was significantly improved in both intervention groups during the first and the second month after the treatment. In the Vitex agnus and Flaxseed groups, the mean total PMS scores were significantly lower than those of the control group that received placebo after the treatement (adjusted mean difference: -3.3 (95% CI: -4.0 to -2.1); -4.3 (-5.5 to -3.0), respectively). In the second month after the intervention, the mean total PMS score was -5.8 (-7.0 to -4.7) in the Vitex agnus group and -6.6 (-8.1 to -5.7) in the Flaxseed group. There was no significant difference between the Vitex agnus and Flaxseed groups in terms of the PMS score. Only one person in Vitex agnus group reported mild nausea.

The effect of Echinophora platyloba on PMS
Delaram reported there was no significant difference in severity of PMS between two groups before the intervention, while a significant difference was observed after the intervention (p=0.002). Also, the severity of anxiety and depression in intervention groups was significantly lower than the placebo group. The participants in the E. platyloba group reported reductions in the severity of symptoms, with the most marked reduction being seen in depression (p=0.029) and anxiety (p<0.001) symptoms. Two participants complained of an unpleasant taste, nausea and vomiting (Delaram, 2014).

The effect of Fennel (Foeniculum vulgare) on PMS
Delaram and Heydarnejad found a significantly greater improvement in combined symptoms (stress, depression, excitement, somatic and cluster symptoms) in the treatment group than placebo of the fennel (p<0.05) except for the bloating which was unaffected by the treatment. The reductions in the percentages of all symptom scores in the treatment group were significantly more pronounced than the placebo group. There were few adverse events such as visual symptoms related to consumption of fennel extract in one person (Delaram and Heydarnejad, 2011) The effect of valerian root extract on PMS Two trials , Kamranpur et al., 2015 determined the impact of valerian on PMS. In one trial done by Kamran pour et al., according to Friedman test, there was a significant difference in the severity of mood, physical and behavioral symptoms among baseline, 4 weeks and 8 weeks after taking valerian in both intervention and placebo (50 mg starch) groups (p<0.001) and this difference was more pronounced in experimental group than placebo.
In another study done by Behboodi Moghadam et al., results showed a significant difference in mean severity of premenstrual mood (p<0.001) and behavioral (p<0.001) symptoms in the valerian group compared to placebo, before and after the intervention. Moreover, the difference in mean score of mood and behavioral symptoms was significant among baseline, and one, two, and three months after the intervention in treatment group (p<0.001). Nevertheless, this difference was insignificant in the control group.

The effect of orange peel essence (Citrus sinensis) on PMS
In one trial done by Ozgoli et al., the rates of reduction in severity of PMS symptoms were 46.08% and 14.21% after using the essence of citrus, and the placebo (water and sugar), respectively. There was a significant difference between two groups regarding the rate of reductions in severity of PMS symptoms (p<0/001). Also, reductions in severity of physical symptoms were 24.30% in the case group and 5% in the placebo group. The rate of reduction in severity of psychological symptoms were 21.78% in the case group and 9.21% in the placebo group (p<0/001). Moreover, 94.7 % in treatment group and 100% in placebo group did not report any side effects (Ozgoli et al., 2012) The effect of Hypericum perforatum on PMS Two trials (Pak Gohar et al., 2006;Kheirkhah et al., 2013) checked the effect of Hypericum perforatum (perforan) on the PMS. Kheirkhah et al. found a decrease in symptoms in treatment group comparing to the placebo group. In this regard, the mean of severity was 23.64 in the perforan-treated group, and 46.37 (p=0.001) in the placebo group. There were no side effects in both groups. In another trial done by Pak Gohar et al., the rates of reductions in severity of PMS symptoms were 46.45% in group treated with H. perforatum and 18.1% in placebo group. Thus, the rates of reduction in severity of PMS symptoms in intervention groups were significantly more marked than the placebo group (p=0.000).

The effect of ginger on PMS
In one trial done by Khayat et al., there was a significant difference between the two groups in terms of overall severity of PMS and severity of physical, mood and behavioral symptoms after intervention (p<0.001). Ginger significantly reduced overall severity of PMS and severity of physical, mood and behavioral symptoms (p<0.001). One subject in the intervention group experienced gastrointestinal side effects (Khayat et al., 2015).

Discussion
The current evidence underlines the essential role of serotonergic system during the luteal phase in women experiencing PMS. Likewise, the effect of sexual hormones on the uptake, binding, turnover, and transportation of serotonin has been reported (Halbreich et al., 2003).
It has been suggested that dysregulation of the serotonergic system, specifically alterations in serotonin activity, is responsible for most PMS symptoms (Andrus, 2001). Reviewing these studies indicated that most of these Iranian herbal plants possess antidepressant effects through a serotonergic mechanism and their anti-inflammatory effects can reduce general symptoms of PMS, especially the psychological signs. Modes of action of these herbal medicines are shown in Table  3. In this way, the present investigation reports that the importance of serotonergic operators in the treatment of PMS (Dimmock et al., 2000). our research evaluated modes of action of herbal medicines on PMS and in clinical practices, chemical drugs such as mefenamic acid and fluoxetine are effective in reduction of PMS symptoms through mechanisms mentioned above (Brown et al., 2009). Review showed that in the control group, there was also a decline in the severity of symptoms. Several factors may be involved in placebo response, including doctor-patient relationship, patients' positive or negative expectations of treatment, cultural factors like patients' perception of colors, forms, and drug names, along with their experience and perception of fate and faith (Moerman, 2000, Del Giorno et al., 2010. This systematic review showed that placebo had a slight effect on alleviating PMS symptoms. One possible explanation for this can be cultural difference between participants. Since the investigations in assessing the treatments of PMS without the utilization of control group and placebo are under serious questions. Indeed, even in randomized clinical trials, the placebo reactions must be reduced. Follow-up of women for more than three menstrual cycles can confine the placebo responses in PMS interventional studies (Zomorodian et al., 2011).
In the current systematic review, the length of treatments (three menstrual cycles) might not be adequate to minimize the placebo impact. Except four study (Sodouri et al., 2013, Moosavi et al., 2014, Akbarzadeh et al., 2015, Kamranpur et al., 2015 which did not mention the side effects resulting from the use of medicinal plants, in other studies, side effects were not observed or had low-intensity and observed in less than 20% of the cases (Table 2). Some studies showed that side effects of herbal products are less common than synthetic drugs (Younesi, 2014;Karimi etal.,2015). Since, chemical drugs have side effects So, medicinal plants can be an alternative for chemical drugs in PMS treatment. However, medicinal plants should be recommended by physicians when an individual suffers from a special disease or is using other drugs.
Many studies have shown beneficial effects of herbal medicine in decreasing hot flashes. Future studies can compare the effectiveness of Iranian herbal medicines with native plants of other countries and with other methods suggested by alternative medicines for treatment of PMS. Further studies are required to compare side effects (safety) and efficacy of herbal remedies with those of the synthetic drugs. Trials should be comprehensively addressed and investigated in detail as completely as possible, conforming to the CONSORT guidelines (Dworkin et al., 2010) Also, Future trials should construct their plan with respect to CONSORT guideline in order to increase the quality of the trials. Also, further investigations with larger sample size, among females from different socioeconomic levels of the community, using different doses of herbal medicine for longer periods of time as well as studies without using a placebo, are suggested to achieve more definitive results about the effectiveness and safety of herbal medicine for alleviating PMS symptoms.
Although we believe our search was comprehensive, publication bias as a problem in all medical research, may have affected our evaluations (Easterbrook et al., 1991) and this issue may be intensified in alternative medicine research (Ernst and Pittler, 1997). It has also been argued that a narrative summary is susceptible to bias, subjectivity, and limited in the absence of an effect size (Graham, 1995). In order to minimize this possibility, two reviewers discussed the study findings and quality indicators in depth, as well as the potential impact of methodological shortcomings, resolving discrepancies with the third reviewer if necessary. The weak methodology of many studies included in our systematic review can be one of the potential limitations of this study. Small sample sizes, inadequate treatment allocation, unclear blinding method and unmentioned randomization technique may influence the validity of the results.
This research demonstrated the efficacy of herbal medicines in alleviating PMS symptom (Adib-Hajbaghery and Hoseinian, 2014, Menati et al., 2014). Therefore, herbal medicines can be considered as an appropriate alterative for women experiencing PMS